In recent years, management of opportunistic infections has become more and more significant because of an increase in the number of elderly people and immuno-compromised patients as a result of advanced chemotherapies and the like. As demonstrated by the fact that opportunistic infections are occurring one after another by different avirulent pathogen, it is shown that the problem of infectious disease will not end as long as there are underlying diseases that diminish the immune functions of patients. Consequently, new strategies for infectious diseases control, including the problem of drug-resistant pathogens, will be one of the important issues in the imminent aged society.
In the field of antifungal agents, heretofore, for instance, amphotericine B which is based on a polyene skeleton, fluconazole, itraconazole and voriconazole which are based on an azole skeleton, or the like, have been developed for the treatment of deep seated mycoses. Most of pre-existing drugs already available commercially have similar mechanism of action, and currently, the appearance of azole-resistant fungi or the like has been problems.
In recent years, as a 1,3-β-glucan synthetase inhibitor with a novel mechanism, naturally occurring compound-derived cyclic hexapeptides caspofungin and micafungin or the like, have been developed; however, from the fact that these agents only exist in injectable form, they are not yet sufficient practically as antifungal agents.
Since there have been the situations that the pre-existing antifungal agents are insufficient for treatment of the deep seated mycoses, there is a demand and need for development of agents which are based on a novel mechanism and are of high safety.
As the related art relevant to antifungal agents based on such a novel mechanism, Patent Documents 1 and 2 describe pyridine derivatives which demonstrates effects against the onset, progress, and persistence of infections by inhibiting the expression of cell wall proteins, inhibiting the cell wall assembly and also adhesion onto cells, and preventing pathogens from showing pathogenicity, with the process which transports GPI (Glycosylphosphatidylinositol)-anchored proteins to the cell wall being inhibited.
However, groups of the compounds disclosed in Patent Document 1 have 2-benzyl pyridine moieties as the common structure, clearly differing structurally from compounds according to the present invention. In addition, the groups of the compounds disclosed in Patent Document 1 bear the problem that, although these compounds demonstrate activities in vitro, they are easily metabolized inside the body. The group of compounds disclosed in Patent Document 2 exhibits excellent antifungal activity, but has the structure represented by the following formula:
Looking only at those having pyridine ring skeletons, this group differs structurally from the compounds according to the present invention in that the common structure has a single ring bound via an amidomethylene linker at the pyridine ring 3-position.
Patent Documents 3 to 5 also provide examples of related art with structures similar to the compounds according to the present invention. Patent Documents 3 and 4 describe pyridine derivatives substituted by a pyrazole ring, which are used as glycine transporter inhibitors or 5-HT receptor ligands, while Patent Document 5 describes 5-member heterocyclic substituted pyridine derivatives which are used as an AGE disrupter and inhibitor.
Patent Document 6 also describes improving water-solubility by introducing a phosphonoamino group into a morpholine compound that is a tachykinin receptor antagonist, thereby converting it into a prodrug. Additionally Non-Patent Document 1 describes improving water-solubility by introducing a phosphonoamino group into a cephalosporin compound that is an anti-MRSA drug, thereby converting it into a prodrug.
However, Patent Documents 3 to 5, and Non-Patent Document 1 do not describe the compound according to the present invention, and moreover the compounds disclosed in Patent Documents 3 to 5, and Non-Patent Document 1 are not described as having an anti-fungal effect against common agents of human fungal disease such as Candida, Aspergillus and Cryptococcus.     [Patent Document 1] International Publication WO 02/04626 pamphlet    [Patent Document 2] International Publication WO 05/033079 pamphlet    [Patent Document 3] International Publication WO 03/031435 pamphlet    [Patent Document 4] International Publication WO 04/089931 pamphlet    [Patent Document 5] International Publication WO 02/085897 pamphlet    [Patent Document 6] U.S. Pat. No. 5,691,336    [Non-Patent Document 1] Bioorganic & Medicinal Chemistry 11 (2003), 2427-2437